Many people know about amyotrophic lateral sclerosis (ALS, commonly known as Lou Gehrig’s disease after the US baseball player who contracted it in 1939) thanks to the Ice Bucket Challenge that went viral a few years ago. People poured a bucket of ice water over their own or another’s head to promote donations to research.
The incurable neurological condition, which affects about one in 50,000 people, gradually paralyzes patients, halting the ability to speak, eat, move and even breathe, usually killing them within about four years.
One of the symptoms is inflammation connected to the dying neurons, caused by immune mechanisms in the brain. The famed theoretical physicist Prof. Stephen Hawking was unusual, having been diagnosed in 1963 when he was just 21 years old. He survived for 55 years with the incurable condition until he died four years ago.
For most ALS genes, only one mutated copy – a “dominant gene” – is needed to cause disease. For other genes, both copies – “recessive genes” – must be mutated to cause the disease. About 60% of patients with familial ALS have an identified genetic mutation. Yet the vast majority of cases are called sporadic (or singleton), meaning a person with ALS does not have a family history of ALS.
About two-thirds of individuals with familial ALS and 10% with sporadic ALS with no known family history have a known ALS-associated genetic mutation.
Mutations in over 25 genes are involved in ALS, and they all increase the risk of developing it. Now, a research team headed by Prof. Eran Hornstein of the Weizmann Institute of Science in Rehovot and colleagues in the molecular neuroscience and molecular genetics departments have linked a new gene to ALS, but this one contains mutations that are different, as they seem to play a defensive, rather than an offensive, role.
Their findings have just been published in Nature Neuroscience. The gene newly found to involve ALS is located in the part of our genome once called “junk DNA” that comprises over 97% of the genome, but because it does not encode proteins, it used to be considered unimportant and overlooked in the search for the genetic origins of neurodegenerative diseases like ALS.
Today, though this noncoding DNA is still regarded as biological dark matter, it’s already known to serve as a crucial instruction manual that determines when genes that do encode proteins are turned on and off.
“Our brain has an immune system,” explains Dr. Chen Eitan, who led the study in Hornstein’s lab together with Aviad Siany. “If you have a degenerative disease, your brain’s immune cells, called microglia, will try to protect you, attacking the cause of the neurodegeneration.”
The problem is that in ALS, the neurodegeneration becomes so severe that the chronic microglial activation in the brain rises to extremely high levels, turning toxic. The immune system thus ends up causing damage to the brain it set out to protect, leading to the death of more motor neurons.
The Rehovot scientists focused on a gene called IL18RAP, long known to affect microglia (cells in the brain and spinal cord that remove damaged neurons and infections) and found that it can contain mutations that mitigate these cells’ toxic effects. “We have identified mutations in this gene that reduce inflammation,” Eitan said.
After the team analyzed the genomes of 6,000 ALS patients and 70,000 people without ALS, they concluded that the newly identified mutations reduce the risk of developing ALS nearly fivefold; it is extremely rare for such patients to have these protective mutations, and those rare patients who do harbor them tend to develop the disease roughly six years later than those without the mutations – proving that the mutations slow the disease down.
“We’ve found a new neuroprotective pathway,” concluded Eitan, “and future studies can check whether modulating this pathway has a positive effect. Scientists should not ignore non-coding regions of DNA – not just in researching ALS but also other diseases with a genetic component.”